title: Recipient leukocyte infusion enhances the local and systemic graft-versus-neuroblastoma effect of allogeneic bone marrow transplantation in mice.
abstract: Allogeneic hematopoietic stem cell transplantation and donor leukocyte infusion (DLI) may hold potential as a novel form of immunotherapy for high-risk neuroblastoma. DLI, however, carries the risk of graft-versus-host disease (GvHD). Recipient leukocyte infusion (RLI) induces graft-versus-leukemia responses without GvHD in mice and is currently being explored clinically. Here, we demonstrate that both DLI and RLI, when given to mixed C57BL/6→A/J radiation chimeras carrying subcutaneous Neuro2A neuroblastoma implants, can slow the local growth of such tumors. DLI provoked full donor chimerism and GvHD; RLI produced graft rejection but left mice healthy. Flow cytometric studies showed that the chimerism of intratumoral leukocytes paralleled the systemic chimerism. This was associated with increased CD8/CD4 ratios, CD8+ T-cell IFN-γ expression and NK-cell Granzyme B expression within the tumor, following both DLI and RLI. The clinically safe anti-tumor effect of RLI was further enhanced by adoptively transferred naïve recipient-type NK cells. In models of intravenous Neuro2A tumor challenge, allogeneic chimeras showed superior overall survival over syngeneic chimeras. Bioluminescence imaging in allogeneic chimeras challenged with luciferase-transduced Neuro2A cells showed both DLI and RLI to prolong metastasis-free survival. This is the first experimental evidence that RLI can safely produce a local and systemic anti-tumor effect against a solid tumor. Our data indicate that RLI may provide combined T-cell and NK-cell reactivity effectively targeting Neuro2A neuroblastoma.
authors.affiliation: Laboratory of Experimental Transplantation, KU Leuven, Herestraat 49, box 811, 3000, Leuven, Belgium, leen.willems@med.kuleuven.be.
authors.forename: Leen
authors.initials: L
authors.lastname: Willems
authors.forename: Sabien
authors.initials: S
authors.lastname: Fevery
authors.forename: Ben
authors.initials: B
authors.lastname: Sprangers
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: Caroline
authors.initials: C
authors.lastname: Lenaerts
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Ibrahimi
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Stefaan
authors.initials: S
authors.lastname: Van Gool
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
authors.forename: An D
authors.initials: AD
authors.lastname: Billiau
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D006084:Graft Rejection / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D006789:Host vs Graft Reaction / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D017708:Leukocyte Transfusion / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018183:Transplantation Chimera / Q000276:immunology; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D007371:Interferon-gamma; D053804:Granzymes